Fatty Acid Oxidation in Skeletal Muscle

When fatty acids are transported into skeletal muscle they are partitioned into one of two pathways: synthesis, resulting in formation of IMTG, or oxidation, resulting in energy production. Under normal conditions, most fatty acids are shunted towards oxidation, but evidence demonstrates this is not always the case in obesity. A reduced ability to oxidize free fatty acids is a probable explanation for an accumulation of IMTGs and lipid intermediates found in the skeletal muscle of obese individuals. Obesity is also associated with a large surplus of fat, both in storage, adipose tissue, and in circulation (plasma free fatty acids). Therefore, decreased fat oxidation in skeletal muscle likely plays a role in dislipidemia and obesity.

Several studies have examined the impact of obesity on lipid metabolism at the whole-body level. Some studies show no difference or an increase in fat oxidation in obese compared to nonobese subjects,4654 104 107 however, other studies have demonstrated that rates of whole-body fat utilization are lower in obese than nonobese subjects.85113 Because these measures were obtained at the whole-body level, it is difficult to ascertain the effect of other tissues, including liver and adipose, on these results.

Kelley et al.55 examined fatty-acid uptake and indirect calorimetry across the leg in a large sample of obese and nonobese subjects. This model allowed for a measure of metabolism across the muscle of the leg without a large degree of interference from other tissues. Respiratory quotient (RQ, obtained from arterio-venous samples) was significantly higher in obese than nonobese subjects, indicating reduced fatty-acid utilization with obesity. Basal RQ values also correlated indirectly with the insulin sensitivity of the subjects, demonstrating that fat utilization could play a role in IMTG accumulation and insulin resistance.

Fat oxidation in skeletal muscle involves several enzymes, but one of key importance is carnitine palmitoyltransferase 1 (CPT-1). Upon entry of the muscle cell, long-chain fatty acids are first converted to fatty acyl-CoAs in the cytosol and then transported across the outer mitochondrial membrane by the enzyme CPT-1. The activity or ability of CPT-1 to transport fatty acyl-CoAs into the mitochondria is believed to be the rate-limiting step of fat oxidation in skeletal muscle.89 Malonyl coenzyme A (malonyl CoA), the product of acetyl coenzyme A carboxylase (ACC), allostericaly binds to and inhibits CPT-1 activity,74 thereby inhibiting transport of fatty acyl-CoAs into the mitochondria. The importance of the malonyl CoA-CPT-1 interaction upon rates of fat oxidation has been demonstrated in response to many stimuli.84,89,90 Transgenic mice that lack the ACC enzyme (no production of malonyl CoA) have increased rates of fat oxidation and reduced rates of fat storage1. In addition, the same ACC knockout mice are resistant to weight gain and maintain normal insulin sensitivity in response to a high-fat diet.1 An in vivo human study demonstrated that hyperglycemia/hyperinsulinemia decreases long-chain fatty acid oxidation through increasing muscle malonyl-CoA content, but had no effect upon oxidation of medium-chain fatty acids that enter the mitochondria independently of CPT-1.83 The regulation of CPT-1 by malonyl CoA is thus an important regulator of fatty-acid oxidation and also plays a role in metabolic flexibility, which is discussed later. Additional studies have examined this and other enzymes that are important for skeletal-muscle fat oxidation in obesity.

Initial work from our laboratory examined fatty-acid oxidation at the in vitro level in muscle from obese and nonobese subjects. Using a whole homogenate preparation from vastus-lateralis biopsies, we found that obese muscle has a reduced rate of lipid oxidation, as well as reduced CPT-1 and citrate synthase activity.62 In addition, CPT-1 and citrate synthase activities were both inversely correlated with levels of adiposity. Studies from other groups have found similar results, mainly that citrate synthase activity and P-hydroxyacyl CoA dehydrogenase (P-HAD) activity are depressed in muscle from obese/insulin-resistant subjects.100,101,113 In relation to this, muscle from obese/insulin-resistant subjects has been shown to have increased activities of glycolytic enzymes. Simoneau et al. 101 found that the ratio between glycolytic and oxidative enzyme activities within skeletal muscle correlated negatively with insulin sensitivity. These data led us to hypothesize that skeletal muscle from obese subjects possessed a decrement in fatty-acid oxidation, leading to lipids being shunted to the synthetic pathway, resulting in an accumulation of IMTGs and subsequent insulin resistance.

Our lab has also examined lipid metabolism in intact muscle strips (rectus abdominus) obtained from nonobese, moderately overweight, and extremely obese subjects.50 Incubating intact muscle strips allowed for the tracking of labeled palm-itate into synthesis or oxidation. As expected, muscle from extremely obese subjects displayed a decrement in lipid oxidation (58 percent) when compared to muscle from nonobese. The lipids entering extremely obese muscle were preferentially partitioned toward triglyceride synthesis at a rate twofold higher than that found in nonobese muscle (calculated from a ratio of oxidation/storage). However, muscle from moderately overweight individuals had rates of lipid oxidation and synthesis that were equal to that from nonobese muscle. Interestingly, muscle from moderately overweight individuals had the same increased levels of lipid metabolite content (long-chain fatty acyl-CoA) and the same levels of insulin resistance that is observed in muscle from the extremely obese. Therefore, depressed rates of lipid oxidation could not be the only mechanism causing IMTG accumulation in skeletal muscle from obese subjects.